NKT cell-dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs

Morris, Edward S., MacDonald, Kelli P. A., Rowe, Vanessa, Banovic, Tatjana, Kuns, Rachel D., Don, Alistair L. J., Bofinger, Helen M., Burman, Angela C., Olver, Stuart D., Kienzle, Norbert, Porcelli, Steven A., Pellicci, Daniel G., Godfrey, Dale I., Smyth, Mark J. and Hill, Geoffrey R. (2005) NKT cell-dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs. Journal of Clinical Investigation, 115 11: 3093-3103. doi:10.1172/JCI25249

Author Morris, Edward S.
MacDonald, Kelli P. A.
Rowe, Vanessa
Banovic, Tatjana
Kuns, Rachel D.
Don, Alistair L. J.
Bofinger, Helen M.
Burman, Angela C.
Olver, Stuart D.
Kienzle, Norbert
Porcelli, Steven A.
Pellicci, Daniel G.
Godfrey, Dale I.
Smyth, Mark J.
Hill, Geoffrey R.
Title NKT cell-dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs
Journal name Journal of Clinical Investigation   Check publisher's open access policy
ISSN 0021-9738
Publication date 2005-11-01
Sub-type Article (original research)
DOI 10.1172/JCI25249
Open Access Status DOI
Volume 115
Issue 11
Start page 3093
End page 3103
Total pages 11
Place of publication Ann Arbor, MI, United States
Publisher American Society for Clinical Investigation
Language eng
Formatted abstract
NKT cells have pivotal roles in immune regulation and tumor immunosurveillance. We report that the G-CSF and FMS-like tyrosine kinase 3 ligand (Flt-3L) chimeric cytokine, progenipoietin-1, markedly expands the splenic and hepatic NKT cell population and enhances functional responses to α-galactosylceramide. In a murine model of allogeneic stem cell transplantation, donor NKT cells promoted host DC activation and enhanced perforin-restricted CD8+ T cell cytotoxicity against host-type antigens. Following leukemic challenge, donor treatment with progenipoietin-1 significantly improved overall survival when compared with G-CSF or control, attributable to reduced graft-versus-host disease mortality and paradoxical augmentation of graft-versus-leukemia (GVL) effects. Enhanced cellular cytotoxicity was dependent on donor NKT cells, and leukemia clearance was profoundly impaired in recipients of NKT cell–deficient grafts. Enhanced cytotoxicity and GVL effects were not associated with Flt-3L signaling or effects on DCs but were reproduced by prolonged G-CSF receptor engagement with pegylated G-CSF. Thus, modified G-CSF signaling during stem cell mobilization augments NKT cell–dependent CD8+ cytotoxicity, effectively separating graft-versus-host disease and GVL and greatly expanding the potential applicability of allogeneic stem cell transplantation for the therapy of malignant disease.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
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Created: Wed, 09 Nov 2011, 11:27:32 EST by Miss Kristy Reid on behalf of School of Medicine